16 - oxygenated - 20 - methyl - 21 - oic acids and 16 - oxygenated - 17alpha,20 - methylene-21-oic acids of the pregnane series and the 21-lower alkyl esters thereof



United States Patent ABSTRACT OF THE DISCLOSURE Novell6oxygenated-2O-methyI-A -pregnen 21 oic acids and the 2l-1oweralkyl-esters thereof, novel 16- oxygenated-l7m,20wmethy1ene-21-oic acidsof the pregnane series and the 21-lower-alkyl esters, thereof, which areuseful as anti-inflammatory, anti-viral, anti-microbial, hormonal andantibradykinin agents, and processes for their production.

This invention relates to novel 16-oxygenated-20- methyl-A-pregnen-2l-oic acids and lo-oxgenated- 17u,20a-methylene21-oic acids ofthe pregnane series, the 2l-lower-alkyl esters thereof and processes forthe production thereof.

More particularly this invention relates to novel compounds having thefollowing structural formulas:

XOOC

wherein in Formulas A-H, R is OH OH OH OH H =0, or R1 is or=O; RsiS or=0H H H H H R is hydrogen, methyl or fiuoro; R is =0 or R1 O in which R isan alkylene radical containing up to 8 carbon atoms and the attachingoxygen to carbon bonds are separated by a chain of at least 2 and notmore than 3 carbon atoms; R is R is hydrogen or acyl in which acyl isthe acyl radical of a hydrocarbon carboxylic acid of 1 to 12 carbonatoms, inclusive, X is hydrogen or lower-alky1, Y is hydrogen or fiuoroand the 1,2-carbon atoms linkage is a single bond linkage or a doublebond linkage.

In this application the wavy line appearing at the 3-, 5-, and16-p0sitions of the structural formulas indicates that the substituentscan be present in the ct (alpha) configuration, the ,8 (beta)configuration or mixtures thereof and the wavy lines appearing at the20-position indicates that the substituents can be either cis or trans(20-cis or 20- trans) with respect to the C -C bond. The termhydrocarbon carboxylic acid containing from 1 to 12 carbon atoms,inclusive means saturated and unsaturated aliphatic and aromaticcarboxylic acids having the required number of carbon atoms, such asacetic, propionic, butyric, isobutyric, pivalic, valeric, isovaleric,ca-proic, caprylic, decanoic, dodecanoic, acrylic, crotonic, hexynoic,heptynoic, octynoic, cyclobutanearboxylic, cyclopentene carboxylic,cyclohexanecarboxylic, dimethylcyclohexanecarboxylic, benzoic, toluic,naphthoic, ethylbenzoic, phenylacetic, naphthaleneacetic, phenylvaleric,cinnamic, phenylpropiolic, phenylpropionic, p-butoxyphenylpropionic,succinic, glutaric, dimethylglutaric, maleic, cyclopentylpropionicacids, and the like. The term lower-alkyl means an alkyl radicalcontaining from 1 to 8 carbon atoms, inclusive, such as methyl, ethyl,propyl, butyl, amyl, hexyl, heptyl, octyl and isomeric forms thereof.

The compounds of this invention, represented by structural Formulas A-H,above, and those prepared and named in the examples appended hereto, areuseful antiinflammatory, anti-viral, anti-microbial, hormonal andanti-bradykinin agents. The compounds of Formulas A-H stimulate naturalhost-defense mechanisms to infectious disease and virus-inducedprocesses. In addition, the compounds of Formulas A-H antagonize theactions of prostaglandins and of slow reacting substances in anaphylaxisand are thus valuable anti-asthma and anti-allergic agents.

The novel compounds of this invention are useful in the treatment ofanimalsand birds, and are particularly useful in the treatment of humansand valuable domestic animals. They can be administered in conventionaldosage forms, such as pills, tablets, capsules, syrups, or elixirs fororal use, or in liquid forms which are suitable for injectable products.They can also be administered topically in the form of ointments,creams, lotions, and the like, with or without coacting antibiotics,germicides or other materials forming advantageous combinationstherewith. In addition to their usefulness as physiologically andpharmacologically active agents, the compounds of Formulas A-H areuseful as intermediates in the preparation of other useful steroids ashereinafter described.

The essential part of the process of this invention is represented bythe following flow diagram of partial structural formulas:

X1000 II III XOOC

wherein X is hydrogen or lower-alkyl and X is loweralkyl as hereinbeforedefined.

The process of this invention, in its broadest aspect, is applicable to16-oxo-17(20)-pregnen-21-oic acid alkyl esters, having in ring D thestructure represented by I, above, which can have the cis configurationor the trans configuration.

The process of this invention comprises (1) reacting a16-oXo-17(20)-pregnen-21-oic acid alkyl ester (I) with diazomethane toobtain the corresponding diazomethane adduct (II); (2) subjecting thediazomethane adduct thus obtained to pyrolysis to produce thecorresponding 16- oXo-20-methyl-17(20)-pregnene-21-oic acid alkyl ester(III) and the corresponding l6-oXo-17a,20-methylene pregnan (orpregnen)-21-oic acid alkyl ester (IV); and (3) reducing the compounds ofFormulas III and IV thus obtained, with a reducing agent to obtain thecorresponding l6-hydroxy compounds of Formulas V and VI, respectively.The compounds of Formulas III, IV, V and VI wherein X is lower-alkyl canbe hydrolyzed by known methods to obtain the corresponding free 2l-oicacids,

Starting materials which are of particular value in the process of thisinvention are the 16-oXo-17(20)-pregnen- 21-oic acid alkyl estersrepresented by Formula Ia, below:

XOOC H R f I a g 6 Ia RaI ts wherein R R X and Y have the meaningspreviously given and R is :0,

H on@ out t or H H H in which R and R have the meanings previouslygiven, R is hydrogen or hydroxy and wherein the 1,2-, 4,5- and5,6-carbon atom linkages are each single or double bond linkages.Compounds falling Within the scope of Formula Ia, above, which areespecially advantageous as starting materials in the process of thisinvention for the production of the compound of Formulas A-H, above, arethose represented by the following formulas:

wherein in Formulas Ib-Ie, above, R R R R X, Y and the 1,2-carbon atomslinkage have the meanings previously given.

The starting 16-oxo-17(20)-cis and trans-pregnen-Zloic acids and thealkyl esters thereof, used in the process of this invention aredisclosed in Netherlands patent application No. 6,414,319, publishedJune 10, 1965. These starting materials are prepared from thecorresponding 16-desoxy compounds which are either known in the art, seefor example US. Patents 2,790,814 and 3,162,631 or can be prepared fromthe corresponding 20-oxopregnanes in accordance with the proceduresdisclosed therein.

In some instances a mixture of both the cis and trans isomers areobtained in good yields which can be easily separated into the purifiedcis and trans isomeric forms by known methods, for example, thosemethods hereinafter described. In other instances either the cis ortrans isomer predominates and can be easily recovered by known methodsand in these instances the less predominant isomer can be isolated -byrigorous application of known purification procedures, such ascountercurrent distribution, fractional crystallization, chromatography,and the like. Where larger amounts of the less predominant isomer aredesired, it is convenient to isomerize the more readily available isomerto a mixture richer in the less predominant isomer, followed byseparation of the two isomers thus produced. Several isomerizationmethods have been found to be effective. Treatment of a given isomerwith iodide or alkali will produce a mixture containing both cis andtrans isomers. A preferred method is to irradiate the given isomers in asuitable solvent with an intense light source. Thin-layer chromatographyof the solution during the isomerization reaction permits a suitablechoice of conditions and allows the reaction to be terminated when theequilibration has been completed. Elution of the material from thethin-layer spot aifords a purified product. Alternatively columnchromatography will also afford a purified product.

The starting 16-oxo-17(20)-pregnen-2l-oic acid alkyl esters are thusprepared in accordance with Netherlands patent application No.6,414,319, in accordance with the reaction sequence exemplified by thefollowing flow diagram of partial structural formulas:

X1000 H XzOOG 1? :1: Torr i I To (0) wherein X has the meaningpreviously given, and by Preparations 1 and 3 herein. A17(20)-pregnen-2l-oic acid alkyl ester (a) having the cis or transconfiguration, is dissolved in an inert solvent and treated withselenium dioxide to produce the corresponding 16-hydroxy-17(20)-pregnen-Zl-oic acid alkyl ester (b) which is converted by oxidation withchromic acid or activated manganese dioxide to give the correspondingl6-oxo-l7(20)-pregnen- 21 oic acid alkyl ester (c). The starting cis ortrans 16-oxo-17 (20)-pregnen-21-oic acid alkyl esters (c), thusobtained, can likewise as hereinbefore described be isomerized to obtaina mixture of both isomers which can be separated into the purified cisand trans forms by known methods. Irradiation with an intense lightsource and purification as hereinbefore described and as exemplified byPreparation 3 is the preferred method.

Alternatively, the starting materials of the invention having anattached 9a-fluoro substituent can be prepared from the corresponding11,8-hydroxy compounds either before or after the introduction of the16-oxo substituent using conventional procedures for the introduction ofa 9a-fluoro substituent, namely, by reacting the appropriatellfl-hydroxy compound with an N-haloamide or N-haloimide and anhydroussulfur dioxide using the procedure described in US. Patent 3,005,834,treating the corresponding 9(ll)-compound so obtained withN-bromoacetamide and perchloric acid or the like followed by treatmentwith potassium acetate in acetone to form the corresponding 93,1l,8-oxido compound and reacting the latter compound with hydrogenfluoride or hydrogen chloride under anhydrous or aqueous conditions toform the desired 9a-fluoro-1lB-hydroxyand 9tx-chloro-11phydroxycompounds. The 9a-fluoro-llfi-hydroxy and 90achloro-llfl-hydroxycompounds can be oxidized, for example, using chromic acid, sodiumdichromate, and like oxidizing agents, to obtain the correspondingll-oxo compounds.

In carrying out the process of the present invention a16-oxo-17(20)-pregnen-2l-oic acid alkyl ester (I) is dissolved in aninert organic solvent such as benzene, toluene, ylene, and the like andreacted with diazomethane in accordance with the manner of Wettstein(Helv. Chim. Acta, 27, 1803 [1947]) to produce the corresponding17(20)-diazomethane adduct (II). The thusproduced adduct (II) isdecomposed by pyrolysis to obtain a mixture comprising the correspondingl6-oxo-20- methyl-l7(20)-pregnen-21-oic acid alkyl ester (HI) and thecorresponding 16-OX0-17a,200t methylene pregnane (or pregnen)-21-oicacid alkyl ester (IV). The pyrolysis is conveniently and advantageouslycarried out by heating the diazomethane adduct (II) above its meltingpoint, preferably under reduced pressure, until decomposition of the:adduct is complete; a period of about 10 minutes is usually sufiicient.Temperatures greater than 20 C. above the melting point of thediazomethane adduct should be avoided in order to prevent decompositionof the resulting products (III) and (IV). The products (III) and (IV)thus obtained, are recovered from the reaction mixture, separated andpurified by conventional methods such as chromatography and/orcrystallization. from a suitable organic solvent or solvents, forexample, ethyl acetate, cyclohexane, methylene chloride, Skellysolve Bhexanes (hereinafter referred to as Skellysolve B), ether, mixturesthereof and the like.

The compounds of Formulas III and IV, thus obtained, can if desired bereduced to obtain the corresponding 16,8-hydroxy and l6a-hydroxycompounds of Formulas V and VI, respectively, in accordance with methodsknown in the art for reducing secondary hydroxy groups in steroids, forexample, using sodium, potassium or lithium borohydride, lithiumaluminum-tri-methoxy hydride, the corresponding methoxy and ethoxyhydrides and the like. See Djerassi, Steroid Reactions, Holden-Day,Inc., San Francisco, pages -147 (1963). Lithium aluminum-tri-tert.butoxy hydride in tetrahydrofuran is preferred, especially When anll-keto group is present because it gives selective reduction at the 16-position. Solvents other than tetrahydrofuran such as benzene, toluene,ether, dioxane and the like can also be used. The reduction can becarried out at temperatures ranging from about 0 to 40 C. Roomtemperature (about 25 c.) is preferred. The isomeric 16aand 16B- hydroxycompounds so obtained are separated from the reaction mixture andpurified in accordance with methods well known in the art, for example,chromatography and/or crystallization from a suitable organic solventsuch as those hereinbefore listed for the recovery and purification ofthe compounds of Formulas III and IV.

The 2l-oic acid alkyl esters of this invention, for example, thecompounds of Formulas A-H, wherein X is lower-alkyl, can be converted tothe corresponding free 21-oic acids by hydrolysis with a base such asaqueous sodium or potassium hydroxide in accordance with methods knownin the art, for example US. Patent 3,162,631.

In the process of this invention, when a 3-oxo group is present in thestarting material (I) and the corresponding l6-oxo compounds of FormulasIII and IV are to Ibe converted to the corresponding l6-hydroxycompounds of Formulas V and VI, respectively, it is desirable to havethe 3-oxo group, protected, for example, by a cyclic alkylene acetalgroup, in order to prevent concomitant reduction at the 3-position.

The compounds represented by Formulas; C and D of this invention can beconverted to the corresponding A compounds of Formulas A and .B,respectively, by subjecting the compounds of Formulas C and D todehydration in accordance with methods known in the art, for example,using anhydrous hydrogen chloride at low temperatures, about -5 to +5 C.

The A -3-oxo compounds of this invention, such as those represented byFormulas A and B, above, can be prepared by the alternative method ofsubjecting the corresponding A -3-oxo compounds to dehydrogenation atthe 1,2-position by fermentative or chemical methods in accordance withprocedures well known in the art. Fermentative dehydrogenation comprisesthe use of microorganisms such as Septomyxa, Corynebacterium, Fusariumand the like. See for example US. Patents 2,602,- 769, 2,902,410 and2,902,411. Chemical dehydrogenation can be carried out with seleniumdioxide according to known procedures, for example, Meystre et al.,Helv. Chim. Acta, 29, 734 (1956) or with 2,3-dichloro-5,6-dicy'ano-1,4-benzoquinone in a suitable organic solvent such as dioxaneor benzene, see, for example, Djerassi, Steroid Reactions, page 132,Holden Day, Inc., San Francisco (1963).

The compounds of this invention having attached hydroxy substituents atthe 3- and/or 16-positions can be acylated with an acylating agent inaccordance with methods known in the art for acylating steroidalsecondary hydroxy groups, for example, with the acid chloride oranhydride of a hydrocarbon carboxylic acid, such as, those acidshereinbefore listed.

The compounds of this invention having an acyl group present at the3-position can be hydrolyzed to the corresponding free-alcohol, inaccordance with known methods, for example, with an aqueous base such assodium or potassium bicarbonate, aqueous sodium hydroxide and the like.

The 3-oxo compounds of this invention can be ketalized at the 3-positionin accordance with methods well known in the art as illustrated byExamples 21 and 22, herein. The ketalization is carried out by reactingthe selected 3-oxo compound with an alkane-1,2-diol or alkane1,3-diolsuch as ethylene, propylene, trimethylene, 1,2-butylene, 2,4-pentylene,4-methyl 1,2 pentylene, 6- methyl-1,3-hexylene, 1,2-heptylene,3,4-hepty'lene, 1,2- octylene glycol and the like; preferably in anorganic solvent such as benzene, toluene, xylene, methylene chloride,and the like, and in the presence of an acid catalyst such asp-toluenesulfonic acid, benzenesulfonic acid and the like. The reactionis conducted at a temperature between about 20 C. and about 200 C.,preferably between about 70 C. and about 120 C. The time required forthe reaction is not critical and may be varied between about 1 and 48hours, depending on the temperature, the ketalizing agent and catalystemployed.

The compounds of this invention having a cyclic alkylene acetal grouppresent can be hydrolyzed to the free 3-oxo compounds in accordance withprocedures well known in the art, for example, using an aqueous mineralacid such as sulfuric acid, as illustrated by Example 20, herein.

The following preparations and examples are illustrative of the processand products of this invention but are not to be construed as limiting.

PREPARATION 1 Methyl 6,8-ace txy-3 a,5a-cycl0pregn-1 7 (20 -trans-en- 16 -0ne-21 -oate A solution of 8.0 g. of methyl6/3-acetoxy-3aim-cyclopregn-17(20)-cis-en-21-oate in about 400 ml. oftetrahydrofuran was stirred and heated under reflux with 6.0 g. ofselenium dioxide for about 4.5 hours. The excess selenium dioxide wasremoved by filtration through a pad of Celite filter aid. The filtratewas concentrated by distillation in vacuo to a volume of 50 ml. Thismaterial was diluted with 200 ml. of ethyl acetate and washedsuccessively with ice cold freshly prepared ammonium polysulfide, colddilute ammonium hydroxide, cold dilute (2%) hydrochloric acid andfinally saturated aqueous sodium bicarbonate. This solution, with mostof the selenium removed by this treatment was dried over sodium sulfateand concentrated to dryness by distillation in vacuo.

The residue thus obtained was dissolved in ml. of methylene chlorine andchromatographed over 200 g. of Florisil. The product was eluted with 200ml. fractions of 7.5% acetone in Skellysolve B. The crystallinefractions containing the desired product, 5.34 g., were recrystallizedfrom Skellysolve B to give 4.13 g. methyl 6fl-acetoxy-16f3-hydroxy-3m,5u-cyclopregn-17(20)-trans-en-21-oate, M.P. 117 C. Infraredand NMR spectra were in agreement with the structure.

Analysis.Calcd. for C H O C, 71.61; H, 8.51. Found: C, 71.37; H, 8.63.

Methyl 65-acetoxy-16a-hydroxy 30,5oc cyclopregn- 17(20)-cis-en-21-oateis obtained in lesser quantities by additional chromatography.

The methyl 6 3-acetoxy-16fl-hydroxy 3a.,5occyclopregn-l7(20)-trans-en-21-oate thus obtained in about 400 ml. ofethyl acetate is treated with about 18.0 g. of activated manganesedioxide and agitated for about 5 hours at room temperature. The reactionmixture is filtered through a bed of Celite and the residue is rinsedwith hot ethyl acetate. The filtrate thus obtained is concentrated bydistillation in vacuo to a residue which is recrystallized from ethylacetate-Skellysolve B to give methyl 6/8-acetoxy-16-oxo 304,5otcyclopregn-17(20)-trans-en- 21-oate.

In the same manner the corresponding cis isomer can be oxidized toobtain methyl 6B-acetoxy l6 oxo-3a,5acyclopregn-l7(20)-cis-en-21-oate.

The above example typified the procedure disclosed in Netherlands patentapplication No. 6,414,319, supra. The other 16-oxo starting materialsfor the process of the invention, such as those representsed by FormulaIa, above, and those listed in Example 1, below, can likewise beprepared from the corresponding 16-desoxy compounds.

PREPARATION 2 Methyl 3p-hyclr0xy-1 6-0x0-5,17(20)-trans-pregnadiene-ZI-oate A solution of 500 mg. of methyl6B-acetoxy-16fi-dihydroxy-3ot,5ot-cyclopregn-l7(20)-trans-en-2l-oate in25 ml. of acetone was refluxed for one hour with 2 ml. of 10% sulfuricacid. The excess acid was neutralized with aqueous sodium bicarbonate.The product crystallized upon dilution with water and was filtered,washed with deionized water and dried to constant weight in vacuo at 40C. The yield was 490 mg. of methyl36,16,8-dihydroxy-5,17(20)-trans-pregnadien-2l-oate, M.P. -151 C.Infrared spectra supported the structure. Amax, 223, e13,850/EtOH.

Analysis.-Calcd. for C H O C, 73.29; H, 8.95. Found: C, 72.62; H, 9.23.

The methyl 35,16/3-dihydroxy 5,17(20) trans-pregnadien-Zl-oate thusobtained is then treated with activated manganese dioxide in the mannerdisclosed in Preparation 1, above, to obtain methyl3fl-hydroxy-l6-oxo-5,17- (20)-trans-pregnadien-2l-oate.

PREPARATION 3 Methyl 3,16-di0x0-5u-hydr0xy 6B methyl-Sa-[Jregn-U-(20)-trans-en-21-0ate, 3-cyclic 2,2 dimetlzylpropane- 1,3-di0l acetal Asolution of 10.0 g. of methyl 3-oxo-5ot-hydroxy-6B- methyl-Sa-pregn17(20) trans-en-2l-oate, 3-cyclic-2, 2-dimethylpropane-1,3-di0l acetalin 500 ml. of tetrahydrofuran was stirred and refluxed with 7.5 g. ofselenium dioxide for 4.5 hours. The reaction mixture was worked up inthe manner described in Preparation 1, above.

The crude product thus obtained was dissolved in 200 ml. of methylenechloride and chromatographed over 700 g. of Florisil. The product waseluted with 200-ml. portions of 7.5% acetone in Skellysolve B.Crystalline fractions 13 to 20 4.46 g., were combined and recrystallizedfrom ether-Skellysolve B to give 3.24 g. of methyl 3-oxo- 9511,16fl-dihydroxy-6,B-methyl 50c pregn-17(20)-trans-eu- 2l-oate,3-cyclic-2,2-dimethylpropane-1,3-diol acetal M.P. l98203 C. Infrared andNMR spectra support the structure.

Analysis.Calcd. for C gH O -Z C, 70.35; H, 9.30. Found: C, 70.90; H,9.61.

The methyl 3-oxo-5a,16/3-dihydroxy 6Bmethyl-5apregn-17(20)-trans-en-21-oate, 3-cyclic 2,2dimethylpropane-1,3-diol acetal, thus obtained, is treated withactivated manganese dioxide in the manner disclosed in Preparation 1,above, to obtain methyl 3,l6-dioxo-5 x-hydroxy-6 3-methyl-5a-pregn17(20) trans-en-Zl-oate, 3- cyclic-2,Z-dimethylpropane-1,3-diol acetal.

The corresponding cis isomer can be obtained by subjecting the transcompound to isomerization in the manner disclosed in Preparation 4,below.

PREPARATION 4 Methyl 5a-hydro'xy-65-methyl 3,11,16trix0-5a-pregntrans-17(20) -en-21-0ate, 3-cyclic ethylene acetal Asolution of 500 mg. of methyl a-hydroxy-6fl-methyl-3,1l,l6-trioxo-5a-pregn-cis l7(20)-en-2l-oate, 3-cyclic ethylene acetalwas dissolved in about 25 ml. of dry chloroform and irradiated withultraviolet light (a Hanovia U.V. lamp) for 20 hours at roomtemperature. Thinlayer chromatography indicated that two steroids ofslightly different polarity were present. The chromatography was done ona silica gel plate developed in 2:1- cyclohexanezethyl acetate andsprayed with KMnO NaIO reagent [R. U. Lernieux and H. F. Bauer, Anal.Chem. 26, 920 (1954)].

The cholorform solution was mixed with 10 g. of silica gel and thesolvent was removed in vacuo at 40 C. in a drying oven. This materialwas placed on a column of silica gel wet-packed with2:1-cyclohexanezethyl acetate. The column was eluted with 25 ml.portions of this same solvent mixture. The early eluate fractions gave acrystalline product, 0.304 g., which was recrystallized from ether togive 190 mg. M.P. 142145 (3., methyl Sa-hYdl'OXY-Gfimethyl3,11,16-trioxo-5a-pregn-trans-17(20)-en-21-oate, 3-cyclic ethyleneacetal the starting trans isomer. The later eluate fractions gaveanother crystalline product 0.144 g. which was recrystallized from etherto give 80 mg. of methyl5u-hydroxy-6/8-methyl-3,11,16-trioxo-5orpregn-trans 17(20)-en-21-oate,3-cyclic ethylene acetal M.P. 222-225 C. NMR analysis confirmed thestructure.

In the same manner other 20-cis or 20-trans starting materials used inthe process of this invention can be converted to a mixture of thecorresponding cis and trans isomers. The mixture thus obtained canlikewise be separated to give the respective purified cis and transisomeric forms by conventional methods such as chromatography and/ orcrystallization and the like.

ExAMPLE 1 Diazomethane adduct 0 methyl Sa-hyJmxy-tifl-methyl-fi,11,16-trioxo 5u-pregna-17(20)-eis-en-21-0ate, 3 cyclic ethylene acetal Asolution of 30.0 g. of methyl Sa-hydroXy-GB-methyI-3,11,16-trioxo-17(20)-cis-pregnen-2l-oate, 3-cyclic ethylene acetal wasdissolved in about 400 ml. of dry benzene and treated with an excess ofdiazomethane in ether at room temperature for about two hours. A littleacetic acid in ethyl ether was added to decompose any excessdiazomethane. The mixture was washed with aqueous NaHCO and the solventwas evaporated. The residue thus obtained was recrystallized fromether-Skellysolve B to give 26.2 g. of diazomethane adduct of methylSoc-hydroxy-Gfi-methyl 3,11,16 trioxo-5a-pregna-17(20)-cis en-21-oate,3-cyclic ethylene acetal M.P. 141152 C. (dec.).

Analysis.Calcd. for C H O N C, 63.91; H, 7.43; N, 5.73. Found: C, 63.84;H, 7.48; N, 5.92.

EXAMPLE 2 Diazomethane adduct of methyl 5ot-hydr'0ocy-6fl-flu0ro-3,11,16 tri0x0-5wpregn-17(20)-cis-en-2l-0ate, 3-cyclic ethylene acetal Asolution of 15.0 g. of methyl Son-hYdlOXY-GB-fillOl'O- 3,11,16trioxo-5a-pregn-17(20)-cis-en-21-oate, 3-cyclic ethylene acetal in about200 ml. of benzene was treated with an excess of diazomethane in ether.The latter was prepared by adding 30 g. of N-methyl-N'-nitro-N-nitroguanidine in small increments to a cooled (0 C.) mixture of 300 ml. ofether and ml. of 40% potassium hydroxide with good agitation. Thereaction mixture was then allowed to stand for about two hours at roomtemperature. The excess diazomethane was decomposed by adding slowlywith stirring a solution of one part of acetic acid in five parts ofether. The mixture was concentrated to dryness by distillation in vacuoto leave a crystalline residue. Recrystallization from diethyl ethergave 15.95 g. of diazomethane adduct of methyl Sat-hydroxy-6fi-fluoro3,11,16 trioxo-Sa-pregn-l7(20)-cisen- 2l-oate, 3-cyclic ethylene acetalM.P. 166-167" C. (dec.).

Analysis.Calcd. for C H 0 N F: C, 60.84; H. 6.94: N, 5.68; F. 3.85.Found: C, 61.25; H, 6.64; N, 5.77; F 3.89.

EXAMPLE 3 Diazomethane adduct of methyl 5 u-hydr0xy-6fl-methyl-3,11,16-lri0x0-5a pregn 17(20)-trans=-en-21-0ate, 3- cyclic ethyleneacetal A solution of 15.0 g. of methyl 5u-hydroxy-6/3-methyl- 3,11,16trioxo-5u-pregn-17(20)-trans-en-21-oate. 3-cyclic ethylene acetal inbenzene was treated with an excess of dazomethane in the mannerdescribed in Example 2. The crystalline residue thus obtained wastriturated with ether and filtered to give 14.45 g. of diazomethaneadduct of methyl 5a-hydroxy 6,6 methyl-3,11,16-trioxo-5a-pregn- 17(20)-trans-en-21-oate, 3-cyclic ethylene acetal M.P. 2l6-2l=6 C. (dec.).

Analysis.-Calcd. for C26H33O7N2: C, H, N, 5.73. Found: C, 63.84; H,7.26; N, 5.74.

EXAMPLE 4 Diazo-methane adduct of methyl 5a-hydr0xy-6fl-flu0r0-3,

11,16 trioxo-5a-pregm17(20)-trans-en-2J-0ate, 3-cyclic ethylene acetal Asolution of 15.0 g. of methyl 5a-hydroxy-6/8-fluoro-3,11,l6-trioxo-5a-pregn-17(20)-trans-en-21-oate, 3-cyclic ethyleneacetal in benzene was treated with. an excess of diazomethane in themanner described in Example 2. The crystalline residue thus obtained wastriturated with ether, filtered and dried to give 15.5 g. ofdiazomethane adduct of methyl 5ahydroxy-6fl-fiuoro-3,l1,16-trioxo-5u-pregn- 17(20)-trans-en-21-oate,3-cyclic ethylene acetal M.P. 209210 C. (dec.).

Analysis-Calm. for C H O N F: C, 60.84; H, 6.94; N, 5.68; F, 3.85.Found: C, 60.61; H, 6.66; N, 5.56; F, 3.69.

EXAMPLE 5 Methyl 5a-hydr0xy-6fi,20-dimethyl 3,11,16trioxo-Sapregn-17(20)-cis-en: 21 oate, 3-cyclic ethylene acetal andmethyl 50c hydrovcy-6fi-methyl-3J1,16-tri0x0-17a, 20methylene-(20R)-5a-pregnah-21-0ate, 3-cyelic ethylene acetal Thediazomethane adduct of methyl5w-hydroxy-6flmethyl-3,1l,16-trioxo-5a-pregn-l7(20)-cis-en-21-oate, 3-cyclic ethylene acetal (5.25 g.) was pyrolyzed in vacuo at -180 C. forabout 20 minutes. The crude product was taken up in 50 ml. of methylenechloride, adsorbed on 25 g. of silica gel and dried in an oven at 40 C.in vacuo to remove the solvent. The dried silica gel was thenchromatographed by placing it on top of a column of 500 g. of silica gelwet packed in 2:1 cyclohexane-ethyl acetate. The column was eluted withthe same solvent 1 1 mixture in 200 ml. fractions. The fractionsexhibiting the first peak were combined to give 1.36 g. of residuecontaining methyl 5ot-hydroxy-6,8,20-dimethyl-3,l1,16-trioxo-Sa-pregn-17(20)-cis-en-2l-oate, 3-cyclic ethylene acetal. This materialwas triturated with ether and Skellysolve B (1:1) to give 820 mg. ofpartially crystalline material. A crystalline analytical sample of themethyl SOL'hYdI'OXY- 6fl-20-dimethyl 3,11,16trioxo-5a-pregn-17(20)-cis-en- 2l-oate, 3-cyclic ethylene acetal wasobtained from diethyl ether M.P. 228238 G, A 244, e7,600/EtOH.

Arzalysis.-Calcd. for C26H35O7; C, 67.80; H, 7.88. Found: C, 67.71; H,7.78.

The later eluate fractions showing a second peak were combined to give1.8 g. of an amorphous material. This material was taken up in eitherand reprecipitated with hot Skellysolve B to give 430 mg. of methyl5ot-hydroxy-6B- methyl 3.11,16 trioxo l7ot,20-methylene 20R)50cpregnan-21-oate, 3-cyclic ethylene acetal.

Analysis.-Calcd. for C H O C, 67.80; H, 7.88. Found: C, 67.98; H, 8.27.

EXAMPLE 6 Methyl 50c hydrxy-6fl-fltt0r0-3J1,16-lri0x0-20-merhyloz pregn17(20) cis-en-ZI-oate, 3-cych'c ethylene acetal and methyl5a-hydroxy-6fl-fluoro-3J1,16-tri0x0- 1706,20methylene-(20R)-5ot-pregnan-21 -0ate, 3-cyclic ethylene acetal Thediazomethane adduct of methyl 5a-hydroxy-65- fluoro 3,11,16trioxo-5ot-pregn-17(20)-cis-en-21-oate, 3-cyclic ethylene acetal (5.0g.) was pyrolyzed in vacuo at 180-190 C. for 10 minutes, cooled to roomtemperature and the melt was dissolved in about 25 ml. of methylenechloride. The product was adsorbed on about 25 g. of silica gel, driedand chromatographed over 400 g. of silica gel in the manner described inExample 5. The eluate fractions exhibiting the first peak were combinedto give 1.62 g. of non-crystalline material. A sample was crystallizedfrom ether to give methyl 5ot-hydroxy-6B-fiuoro-3, 11,16 trioxo20-methyl-5ot-pregn-17(20)-cis-en-2l-oate, 3-cyclic ethylene acetal M.P.l24125 C.

Analysis-Calcd. for c n omz c, 64.64; H, 7.16; F, 4.09. Found: 0, 64.43;H, 7.02; F, 4.25.

Analysis.-Calcd. for CZ5H33O7FI C, 64.64; H, 7.16; i

F, 4.09. Found: C, 64.69; H, 7.23; F, 4.21.

EXAMPLE 7 Methyl 5oz hydroxy 6fl-flu0r0-3,11,16-tri0x0-17tx,20methylene-(20S) 50c pregnan-ZI-oale, 3-cyclic-ethylene acetal and methyl5a hydr0xy-6B-flu0r0-3,11,16- trioxo 20methyZ-Sa-pregn-I7(20)-trans-en21-0ate, 3-cyclic ethylene acetal Thediazomethane adduct of methyl 5u-hydroxy-6 81 fluoro 3,11,16 trioxo5a-pregn-17(20)-trans-2loate, 3-cyclic ethylene acetal, 10.0 g, waspyrolyzed in vacuo at 220-230 C. for minutes. The product was cooled toroom temperature and dissolved in 75 ml. of methylene chloride. Thematerial was chromatographed over 900 g. of silica gel in the mannerdescribed 11 Example 5. The eluate fractions exhibiting the first peakwere combined to give 2.4 g. of material containing methyl56t-hydroxy-6B- fiuoro 3,11,16 trioxo methyl-5ot-pregn-l7(20)-trans-en-Zl-oate, 3-cyclic ethylene acetal, determined by infraredanalysis and thin-layer chomatography. Additional purification can beaccomplished by rechromatography and crystallization fromacetone-Skellysolve B.

The eluate fractions showing a second peak were combined to give 6.6 g.of crystalline material which was 12 recrystallized fromacetone-Skellysolve B to give 4.65 g. of methyl 50c hydroxy6,8-fluoro-3,11,l6-trioxo-17a,20- methylene (20S) 50 pregnan-21-oate,3-cyclic ethylene acetal M.P. 266267 C. The infrared spectrum was inagreement with the assigned structure.

Analysis.-Calcd. for C H O F: C, 64.64; H, 7.16; F, 4.09. Found: C,65.03; H, 7.64; F, 4.35.

EXAMPLE 8 Methyl 51x hydroxy 6fl-methyl-3,11,16-tri0x0-17a,20methylene-(ZOS)-5ot-pregnan-21-0ate, 3-eyclic ethylene (metal and methyl5a-hydr0xy-6B,20-dimethyl-3,11,16- trioxo 50pregn-l7(20)-trans-en-21-0ate, 3-eyclic ethylene acetal The diazomethaneadduct of methyl 5ot-hydroxy-6B- methyl 3,11,16trioxo-5e-pregn-17(20)-trans-en-2loate, 3-cyclic ethylene acetal (5.0g.) was pyrolyzed in vacuo at 230-245 C. for about 10 minutes. The meltwas cooled to room temperature and dissolved in 25 ml. of methylenechloride. The product was chromatographed over 450 g. of silica gel inthe manner described in Example 5. The eluate fractions exhibiting thefirst peak were combined to give 960 mg. of material comprising methyl5a hydroxy 618, 20-dimethyl-3,ll,16-trioxo-5a-pregn- 17(20) transen-2l-oate, 3-cyclic ethylene acetal, determined by infrared analysisand thin-layer chromatography. Further purification could beaccomplished by chromatography and crystallization fromacetone-Skellysolve B.

The later eluate fractions showing a second peak were combined to give3.8 g. of crystalline product which was recrystallized from ether togive 3.0 g. of methyl SOL-hydroxy methyl3,11,16-trioxo-17a,20-methylene- (20S)-5a-pregnan-21-oate, 3-cyclicethylene acetal M.P. 245-247 C. The infrared spectrum was in agreementwith the assigned structure.

Analysis.-Calcd. for C H O C, 67.80; H, 7.88. Found: C, 67.58; H, 7.97.

In the same manner following the procedure of Examples 1, 2, 3 or 4,above, but substituting as the starting steroid therein other compoundsof Formula I, such as those represented more specifically by Formulas Ibthrough Ie, above, for example:

methyl 50,11B dihydroxy 6 3-methyl-3,16-dioxo-5apregn 17(20)cis-en-21-oate, 3-cyclic ethylene acetal;

methyl 5oz hydroxy 6B-methyl-3,l6-dioxo-5ot-pregn-l7 (20) cisen-21-oate, 3-cyclic-2,Z-dimethyl-propane- 1,3-diol acetal;

methyl llfi-hydroxy-3, 1 6-dioxo-5, 17 (20 -cis-pregnadien- 21-oate,3-cyclic ethylene acetal;

methyl 3,11,16 trioxo 1,4,17(20)-cis-pregnatrien-21- oate;

methyl 3,16 dioxo 11;3-hydroxy-9a-fluoro-5,17(20)-cis-pregnadien-2l-oate, 3-cyclic ethylene acetal;

methyl 3,16 dioxo 1lfi-hydroxy-9a-fluoro-l,4,17(20)-cis-pregnatrien-21-oate;

methyl 6 methyl-9at-fiuoro-11;3-hydroxy-3,16-dioxo-5,17-

(20)-cis-pregnadien-2loate, 3-cyclic ethylene acetal;

methyl 3;? hydroxy 11,16-dioxo-5a-pregn-17(20)-cisen-2l-oate, 3-acetate;

methyl 3,11,16 trioxo 5a-pregn-l7(20)-cis-en-21-oate,

3-cyclic ethylene acetal;

methyl 30c hydroxy 16 oxo-5 8-pregn-17(20)-cis-.en-2loate;

methyl 3a,11;3 dihydroxy 16-oxo-5fl-pregn-17(20)- cis-en-21-oate;

methyl 11,16 dioxo Sat-pregn-17(20)-cis-en-21-oate;

methyl 3(3 hydroxy 16 ox0-5,17(20)-cis-pregnadien- 2l-oate;

methyl 6;? acetoxy 16 oxo-3 u,5a-cyclo-pregn-17(20)- cis-en-21-oate;

and the like, is productive of the corresponding idiazomethane adductsthereof (II), respectively, which are then methyl511,1l,B-dihydroXy-6/8,20-dimethyl-3,l6-dioxo5apregn-l7(20)-cis-en-2l-oate, 3-cyclic ethylene acetal;

methyl 5a hydroxy-3,1-6-dioxo-6B,20-dimethyl-5epregnl7(20)-cis-en-2l-oate, 3-cyclic 2,2 dimethylpropane- 1,3-diolacetal;

methyl 1lfi;hydroxy-3,16-dioxo-20-methyl-5,17(20) cispregnadien-Zl-Oate,3-cyclic ethylene acetal;

methyl 3,11,16-trioxo-20-methyl-l,4,17(2-0 )-cis trien-21-oate;

methyl 3,16-(110XO-11,B-hYCllOXY-9a-flIIOIO-ZO -IIIClZhYI-S,l7-(20)-cis-pregnadien-2l-oate, 3-cyclic ethylene acetal;

methyl 3,1 6-dioxo-l1,8-hydroxy-9a-fluor0-20-methyl 1,4,

17(20)-cis-pregnatrien-2l-oate;

methyl 9e-flu0ro-1 1B-hydroxy-6,20-dimethyl-3,16 dioxo- 5,17(20)-cispregnadien 21 oate, 3 cyclic ethylene acetal;

methyl 3fi-hydroxy-1l, l6-dioxo-20-methyl5a pregn 17-(20)-cis-en-21-oate, 3-acetate;

methyl 3,1 l,l6-trioxo-20 methyl-Sat-pregn-l7(20)-cis-en- 2l-oate,3-cyclic ethylene acetal;

methyl 3oz-hydr0xy-l6-oxo-20-methyl-5fl pregn 17(20)- cis-en-ZlQoate;

methyl 3e,1lfl-dihydroxy-l6-oxo-20 methyl-5,3-pregn 17-(20)-cis-en-2l-oate;

methyl 11,16-dioxo-20-methyl-5a-pregn-17 (20)-cis-en-21- oate;

methyl 3 B-hydroxy-l6-oxo-20-methyl-5 ,17(20)-cis pregnadien-Zl-oate;

methyl 6fi-acetoxy-l6-oxo-20methyl-3a,5a cyclo pregn- 17(20)-cis-en-2l-oate;

pregnaand the corresponding l7a,20-methylene-(20R) compounds (IV):

methyl 5a,l1,8-dihydroxy-6 8-methyl-3,16 dioxo 17a,20-methylene-(20R)-5a-pregnan21-oate, 3-cyclic ethylene acetal;

methyl 5a-hydroxy-6fl-methyl-3,l6-dioxo-17a,20=methylcue-(20R)-5a-pregnan-2l-oate, 3-cyclic-2,2dimethylpropane-1,3-diol acetal;

methyl 1lfi-hydroxy-3,16-dioxo-17a,20-methylene- (20R)- 5-pregnen-2l-oate, 3-cyclic ethylene acetal;

methyl 3,11,16-trioxo-17u,20-methylene-(20R)-1,4 pregnadien-2l-oatc;

methyl 3,16-dioxo-l 1 3-hydroxy-9'a-fluoro-17u,2 O-methylone-(20R-5-pregnen-2l-oate, 3-cyclic ethylene acetal;

methyl 3,16dioxo-1 l B-hydroxy-9a-fiuorol7a,20-methylone-(20R)-l,4-pregnadien-21-oate;

methyl 3,16-dioxo-1l ,6-hydroxy-6-methyl-9a fiuoro 17a,

ZO-methylene-(ZOR)-5-pregnen-21-oate, B-cyclic ethylene acetal;

methyl 3 B-hydroxyl 1,16-dioxol7a,20-methylene- 20R Sa-pregnan-ZI-Oate,3-acetate;

methyl 3,11,16-trioxo-17a,20-methylene-(20R)-5a pregnane2l-oate,3-cyclic ethylene acetal;

methyl 3a-hydroxy-16-oxo-17a,20-methylcne-(20R) 56- pregnan-Z l-oate;

methyl 30;,11 3 dihydroxy l6 x0 1705,20 methylene-(20R)-5;8-pregnan-2l-oate;

methyl 1 1, l 6-dioxo- 1 7a,20-methylene- 20R) Jet-pregnan- 2l-oate;

methyl 3fi-hydroxy-16-oxo-l7a,20 methylene (20R) pregnen-Z 1 -0 ate;

methyl 6/3-acetoxy-16-oxo-17a,20-methylene (20R) 3a,

5a-cyclopregnan-21-oate;

respectively, and the like.

Similarly, the corresponding compounds having the trans configurationare likewise converted to the corresponding 20-methyl-trans and 1704,20methylene (20S) compounds corresponding otherwise to the cis compoundslisted above.

EXAMPLE 9 Methyl 5 0a,] 6B-dihydr0xy-6p,20-dimethyl-3,I I -di0x0 5apregn-17(20) -cis-en-21-0ate, 3-cyclic ethylene acetal A solution wasprepared containing 4.3 g. of methyl5ahydroxy-6p,20-dimethyl-3,l1,l6-trioxopregn-l7(20) cisen-21-oate,3-cyclic ethylene acetal in 65 ml. of tetrahydrofuran (freshly passedover adsorption grade alumina). A slurry of 5.28 g. of lithium aluminumtri-tertiary butoxy hydride in 65 ml. of the treated tetrahydrofuran wasadded to the solution of the steroid and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was cooled to 0 C. bymeans of an ice-salt bath and the excess reducing agent was decomposedby the slow addition of dilute acetic acid (l-10 acetic acid-water). Theacid in turn was neutralized with a little: sodium bicar' bonatesolution. The insoluble inorganic salts were (filtered on a pad ofCelite filter aid and the residue was rinsed with methylene chloride.The filtrates were partitioned between water and methylene chloride andthe organic extract was dried over anhydrous sodium sulfate. The extractwas concentrated to dryness by distillation in vacuo to leave anamorphous residue. This material was readily crystallized from ether togive 2.6 g. of methyl 5a,16fi-dihydroxy-6,8,20=dimethyl-3,l l-dlOXO-SOLpregnl7(20)-cis-en2l-oate, 3-cyclic ethylene acetal MP. 219 225 C.

Analysis.-Calcd. for C H O C, 67.51; H, 8.28. Found: C, 67.61; H, 8.66.

Chromatography of the mother liquors on silica gel is productive of thecorresponding 16a-hydroxy isomer, methyl5a,l6a-dihydroxy-6fi,20-dimethyl-3,l1 dioxo 5o:-pregn-17(20)-cis-en-2l-oate, 3-cyclic ethylene acetal.

Similarly, substituting the corresponding trans isomer as the startingmaterial in Example 9, is productive of methylc,16B-dihYdIOXy-6B,2O-dimethyl-3,ll-CliOXO 5ozpregnl7(20)-trans-en-2l-oate, 3-cyclic ethylene acetal and methyl5a,l6e-dihydroxy-6,8,20-dimethyl-3,11 dioxo5epregn-l7(20)trans-en-21-oate, 3-cyclic ethylene acetal.

EXAMPLE 10 Methyl 5 ,1 6 3-dihydr0xy-6B-fluor0-3,1 I -di0 x0-20-methy l-5 oc-pl'egltrl 7 (20) -cis-en-21 -0ate, 3 -cyclic ethylene acetal Asolution of 6.0 g. of methyl 5a-hydroXy-6p-fiuoro-3,- 11,16 trioxo20-methyl-5a-pregn-17(20)-cis-en-21-oate, 3-cyclic ethylene acetal intetrahydrofuran was reduced with 7.7 g. of lithium aluminum tri-tertiarybutoxy hydride and the product isolated from the reaction mixture inaccordance with the procedure of Example 9, above. The crystallineresidue thus obtained was recrystallized from ether to give 4.7 g. ofmethyl 5a,165-dihydroxy-6 3-fiuoro-3,1l-dioxo-20methyl-Sa-pregn-l7(20)-cis-err-2l oate, 3- cyclic ethyleneacetal M.P. 196198 C.

Analysis.-Calcd. for C H O F: C, 64.36; H, 7.56; F, 4.07. Found: C,64.45; H, 7.80; F, 3.95.

Chromatography of the ether mother liquors on silica gel is productiveof the corresponding 16x-hydroxy isomer, 5a,l6ot dihydroxy6B-fiuoro-3,ll-dioxo-ZO-methyl- 5a-pregn-17(20)-cis-en-21-oate, 3-cyclicethylene acetal.

Similarly, substituting the corresponding trans isomer as the startingmaterial in Example 10, is productive of methyl,5u,l6,8-dihydroxy-6B-fluoro-20-methyl-3,1l-dioxo-5a-pregn-17(20)-trans-en-2l-oate, 3-cyclic ethylene acetal and methyl5a,16a-dihydroxy-66-fluoro-20-methyl-3,1ldioxo-5a-pregn-l7(20)-trans-en-2l-oate,3-cyclie ethylene acetal.

In the same manner substituting as the starting steroid in Examples 9 or10, above, other 16-oxo-20-methyl cis and trans compounds of thisinvention, represented by partial structural Formula III, is productiveof the corresponding 16aand 16;?hydroxy-20-rnethyl cis and transcompounds (V). For example, using the 16-oxo-20-mcthyl-cis compoundslisted in Example 8, above, as the starting steroids, there is obtained:

methyl oc,l 1,8,16,8-trihydroxy-65,20-dimethyl-3-oxo-5 ocpregn- 17-cis-en-21-oate, 3-cyclic ethylene acetal;

methyl 5 a, 16 {3-dihydroxy-6B,20-dimethyl-3 -oxo-5 u-pregn- 17 20-cis-en-2 l-oate, 3-cyclic-2,2-dimethylprop ane- 1,3-diol acetal;

methyl 11B,16fl-dihydroxy-3-oxo-20-methyl-5,17(20)- cis-pregnadien-2l-oate, 3-cyclic ethylene acetal;

methyl 16B-hydroxy-3 ,1 1-diox0-20-methyl-1,4,7 (20 cis-pregna-trien-2 1-oate;

methyl 3-oxo-11,8,16fl-dihydroxy-9a-fiuOrO-ZO-methyl- 5,17 (20)-cis-pregnadien-21-oate, 3 -cyclic ethylene acetal;

methyl 3-oxo-1 1,8,16B-dihydroxy-9ot-fluoro-20-methyl- 1,4,7 20)cis-pregnatrien-Z 1-0 ate,

methyl 3-oxo-1lfl,16;8-dihydroxy-6,20-dimethyl-9tat-fluoro- 5,17 (20)-cis-pregnadien-21-oate, 3-cyclic ethylene acetal;

methyl 313, 1 6,8-dihydroxy-1 1-0xo-20-methyl-5 a-pregn-17(20)-cis-en-21-oate, 3-acetate;

methyl 16 ,8-hydroxy-3 ,11-dioxo-20-methyl-5a-pregn- 17 20 -cis-en-2l-oate, 3-cyclic ethylene acetal;

methyl 3 a, 165-dihydroxy-20-methyl-5fi-pregn- 17 (20) cis-en-21-oate;

methyl 3 11,11B,16fi-trihydroxy-20-methyl-5,8-pregn- 17(20)-cis-en-21-oate;

methyl 16B-hydroxy-11-oxo-20-methyl-5ot-pregn-17(20)- cis-en-21-oate;

methyl 35,16 3-dihydroxy-20-methyl-5,17 (20) -cispregnadien-Z 1-0 ate;

methyl 613-acetoxy- 1 6B-hydroxy-20methyl-3 a, 5 tit-cyclopregn-17(20)-cis-en-21-oate;

and the corresponding isomeric l6a-hydroxy compounds, respectively.

Likewise, the corresponding isomeric trans-16-oX0-20- methyl compoundscan be reduced to obtain the corresponding 16t3-hydroxy and 16a-hydroxycompounds.

EXAMPLE 11 Methyl 5u,16,8 dihydroxy 6,8-mezhyl-3,11-di0x0-1711,20-

methylene-(ZOR)-5a-pregnan-21-0ate, 3-cyclic ethylene acetal A solutionof 3.24 g. of methyl 5tx-hydroxy-6fi-methyl-17a,20-methylene-3,11,16-trioxo-(20R)-5u pregnan 21- oate, 3-cyclicethylene acetal in tetrahydrofuran was reduced with 3.98 g. of lithiumaluminum tri-tertiary butoxy hydride and extracted from the reactionmixture in accordance with the procedure of Example 9, above. Theresidue thus obtained was recrystallized from acetone- Skellysolve B togive 790 mg. of methyl 5ot,16B-dihydroxy-6fi-methyl-3,1l-dioxo-l7a,20-methylene-(20R) 5oz. pregnan-2l-oate,3-cyclic ethylene acetal M.P. ZZZ-224 C.

Analysis.Calcd. for C25H33O72 C, 67.51; H, 8.28. Found: C, 67.19; H,8.47.

Chromatography of the ether mother liquors on silica gel is productiveof the corresponding 16a-hydr0xy isomer, methyl50:,16a-dihydroxide-6;8methyl-17a,20-methylene-3,l l-dioxo-(20R)-5apregnan 21 oate, 3 cyclic ethylene acetal.

EXAMPLE 12 Methyl 50:,166 dihydroxy 65 flu0r0-3,I1-di0x0-17a,20-

methylene-(20R)-5a-pregnan-21-0ate, 3-cyclic ethylene acetal A solutionof 2.0 g. of methyl 5ot-hydroxy-6B-fluoro- 3,11,16 trioxo 17,20methylene-(20R)-5a-pregnan-21- oate, 3-cyclic ethylene acetal intetrahydrofuran was reduced with lithium aluminum tri-teritary butoxyhydride and isolated from the reaction mixture in accordance with theprocedure of Example 9, above. The residue thus obtained withrecrystallized from ether to give 1.65 g. of methyl 5a,16B dihydroxy 6,8fiu0ro-3,11-dioxo-17a,20-

16 methylene-(20R)-5a-pregnan-2l-oate, 3-cyclic ethylene acetal M.P.265-266 C.

Analysis-Calm. for C25H35O7FZ C, 64.36; H, 7.56; F, 4.07. Found: C,64.10; H, 7.37; F, 4.16.

Chromatography of the ether mother liquors on silica gel is productiveof the corresponding 16a-isomer,SOL-tdihydroxy-6p-fluoro-3,11-di0xo-17u,20-methylene- (20R)Sa-pregnan-ZI-O'ate, 3-cyclic ethylene acetal.

EXAMPLE 13 Methyl 506,1 65-dihydr0xy-6fi-fluoro 3,11 dioxo-I 711,20-

methyZene-Su-(ZOS)-pregnan-2l-0ate, 3-cyclic ethylene acetal and methyl5u,16a-dihydroxy-613 fluoro 3,11-dioxo-I7a,20-methylene-5a-(20S)-pregnan-21 oate, 3- cyclic ethyleneacetal A solution of 2.0 g. of methyl 5a-hydroxy-6p-fluoro-3,11,16-trioxo-17a,20-methylene 5oz (2OS)-pregnan-21- oate, 3-cyclicethylene acetal in tetrahydrofuran was treated with 2.46 g. of lithiumaluminum tri-tertiary butoxy hydride and the products separated from thereaction mixture in the manner described in Example 9, above. Theresidue thus obtained was redissolved in methylene chloride (10 ml.) andthe solution was adsorbed on 25 g. of silica gel and the solvent removedat 40 C. in vacuo. The material was placed on top of a column of 200 g.of silica gel wet packed in 2-1 ethyl acetate-cyclohexane. The columnwas eluted with the same solvent system. The eluate fractions exhibitingthe first peak were combined and the solvent removed to give 770 mg.which was recrystallized from ether to give 560 mg. of methyl5a,16a-dihydroXy-6fi-fluoro-3,11-dioxo-17a, 20-methylene-5a- (20S)-pregnan-21-oate, 3-cyclic ethylene acetal M.P. 208-211 C. Infrared andNMR spectra confirmed the structure.

Analysis.Calcd. for C H O F: C, 64.36; H, 7.56; F, 4.07. Found: C,64.13; H, 7.38; F, 4.02.

The fractions showing a second peak were combined and the solventremoved to give 160 mg. of methyl 50:,166-dihydroxy-6p-fluor0-3,11-dioxo-17a,20 methylene 5a-(20S)-pregnan-2l-oate, 3-cyclic ethylene acetal M.P. 246-250 C. Infraredand NMR spectra were consistent with the assigned structure.

Analysis.--Calcd. for C H O F: C, 64.36; H, 7.56; F, 4.07. Found: C,64.00; H, 7.42; F, 4.05.

EXAMPLE 14 Methyl 5a,] 6a-dihydr0xy-6 3-methyl-3,11 di0x0-17a,20-

methylene 5a-(20S )-pregnan-21-0ate, 3-cyclic ethylene acetal and methyl5a,]6fl-dihydr0xy-6,8-methyl-3,1I-diox0-17a,20-methylene-5a-(20S)pregnan-ZI oate, 3- cyclic ethylene acetal A solution of 2.0 g. ofmethyl 5a-hydroxy-6/3-methyl- 3,11,16-trioxo 1711,20methylene-5a-(20S)-pregnan-21- oate, 3-cyclic ethylene acetal intetrahydrofuran was treated with 2.46 g. of lithium aluminumtri-tertiary butoxy hydride, and the products separated from thereaction mixture and chromatographed in the manner in Examples 9 and 13,above. The eluate fractions showing the first peak were combined and thesolvent removed by distillation in vacuo to give 638 mg. which wasrecrystallized from ether to give 370 mg. of methyl 5a,16a-dihydroxy-6ti-methyl 3,11 dioxo-17a,20-methylene-5a-(20S)-pregnan-Zl-oate,3-cyclic ethylene acetal M.P. 210-212 C. Infrared and NMR spectraconfirmed the structure.

Analysis.--Calcd. for C26H33O7: C, 67.51; H, 8.28. Found: C, 67.62; H,8.26.

The later eluate fractions showing a second peak were combined and thesolvent removed as above to give 489 mg. which was recrystallized fromether to give 300 mg. of methyl 5a,16,8-dihydroxy-6 8-methyl3,1l-dioxo-17a, ZO-methylene 5a (20S)-pregnan-21-oate, 3-cyclic ethyleneacetal M.P. 204-206 C. Infrared and NMR analyses confirmed thestructure.

Analysis.-Calcd. for C26H33O7: C, 67.51; H, 8.28. Found: C, 67.27; H,8.55.

In the same manner substituting as the starting steroid in Examples 11,12, 13 or 14, other 16-oxo-17a,20-methylene cis-(ZOR) and trans-(20S)compounds of this invention, represented by partial structural FormulaIV is productive of the corresponding 16% and 16B-hydroxy-17a,20-methylene cis-(ZOR) and trans-(20S) compounds of Formula VI. Forexample, using the 16-oxo-17a,20 methylene-(20R) compounds listed inExample 8, above, as the starting steriod, there is obtained:

methyl 50,1113,16fi-trihydroxy-GQ-methyl-Zi-oxo-17a,20-

methylene-(20R)5a-pregnan-21 oate, 3-cyclic ethylene acetal;

methyl5a,l6fl-dihydroxy-6B-methyl-3-oxo-17a,20-methylene-(20R)-5a-pregnan-21-oate,3-cyclic 2,2 dimethylpropane-1,3-diol acetal;

methyl 11fl,16,8-dihydroxy-3 -oxo-17a,20-methylene-(20R)-5-pregnen-21-oate, 3-cyclic ethylene acetal;

1,4-pregnadien-2l-oate;

methyl3-oxo-11,8,16fi-dihydroxy-9a-fluoro-17a,20-methylene-(20R)-5-pregnen-21-oate,3-cyclic ethylene acetal;

methyl 3-oxo-1 1,9,16 8-dihydroxy-6-methyl-9a-fluoro-17a,ZO-methylene-(20R)-5-pregnen-21-oate, 3-cyclic ethylene acetal;

methyl 3 8, 1 6p-dihydroxy-1 1-oxo-17a,20-methylene-(20R)-5a-pregnan-2l-oate, 3-acetate;

methyl 16B-hydroxy-3,11-dioxo-17a,20-n1ethylene-(20R)-Swpregnan-Zl-oate, 3-cyclic ethylene acetal;

methyl 30a, 1 6 8-dihydroxy- 1 7a,20-methylene- 20R) -55-pregnan-Zl-oate;

methyl 3u,11B,16/i-trihydroxy-17a,20-methylene-(2OR)-5/3-pregnan-21-oate;

methyl l6/3-hydroxy-l l-oxo-17a,20-methylene-(20R)- 5a-pregnan-2l-oate;

methyl 3 ,8,16,8-dihydroxy-l7a,20-methylene-( 20R) -5- pregnen-Zl-oate;

methyl 6,8-acetoxy-16,8-hydroxy-17a,20-methylene-(20R)-3a,5a-cyclo-pregnan-2l-oate;

and the corresponding isomeric 16a-hydroxy compounds, respectively.

Similarly the corresponding isomeric 1705,20-11'16thY1- cue-(20S) (IV)compounds can likewise be converted to the respective corresponding16aand 16fl-hydroxy Compounds VI.

EXAMPLE 15 Methyl 6a,20-dimethyl 16/3-hydr0vcy-3JI-dioxopregna- 4,1 720) Cl S-d iert-21 -ate A solution of 1.32 g. of methyla,16;8-dihydroxy-6B, 20 dimethyl 3,11 dioxo- 5ozpregn-l7(20)-cis-en-2loate 3-cyclic ethylene acetal was dissolved inabout 50 ml. of chloroform and cooled to about -5 C. Anhydrous hydrogenchloride was bubbled into the mixture slowly for about 2 hours at -5 to0 C. The mixture was then poured into crushed ice and excess sodiumbicarbonate solution, shaken, the organic layer separated, dried overanhydrous sodium sulfate and concentrated to dryness by distillation invacuo. The crude product was recrystallized from ether to give 680 mg.methyl 6a,20-dimethyl-16fihydroxy 3,11- dioxopregna4,17(20)-cis-dien-21-oate M.P. 190-193 C. A max. 236, ,e 18,750/EtOH.Infrared spectra was in agreement with the structure.

Analysis.-Calcd. for C H O C, 71.97; H, 8.05. Found: C, 71.35; H, 8.30.

In the same manner substituting the corresponding trans isomer as thestarting steroid in Example 15, there is obtained methyl 6u,20 dimethyl16B hydroxy-3,11- dioxopregnal,17(20)-trans-dien-21-oate.

EXAMPLE 16 A solution of 1.0 g. of methyl 5a,l6;8-dihydroxy-6/8- fluoro3,11 dioxo 20 methyl 5a mega-17(20)- cis-en-21-oate, 3-cyclic ethyleneacetal in 50 ml. of chloroform was cooled to -5 C. in an ice-salt bath.Anhydrous hydrogen chloride was bubbled into the mixture slowly for 2hours while the temperature was maintained at -5 to 0 C. The mixture waspoured into crushed ice and excess sodium bicarbonate solution. Themixture was shaken to complete the neutralization of the excesshydrochloric acid and organic phase was separated and dried overanhydrous sodium sulfate. The extract was concentrated to dryness bydistillation in vacuo to leave a light yellow amorphous glass which wasdissolved in ether and crystallized to give 630 mg. of methyl 6::fluoro-3,11- dioxo 16B hydroxy 20 methylpregna 4,17(20)-cis dien-21-oateM.P. 1395-198 C., A max. 231, e 17,200/ EtOH.

Anwlysz's.-Calcd. for C H O F: C, 68.29; H, 7.23; F, 4.69. Found: C,68.44; H, 6.82; F, 4.51.

In the same manner substituting the corresponding trans isomer as thestarting steroid in Example 16 there is obtained methyl 60c fluoro 3,11dioxo-16fi-hydroxy- 20-methylpregna-4, 17 (20 -trans-dien-2 l-oate.

EXAMPLE 17 Methyl 16,8-hydr0xy-3,11-di0x0-6a-methyl-J 7 0:,20-methylene- (20R) -4-pregnen 2I-0ate* A solution of 1.0 g. of methyl5a-16 3-dihydroxy-3,11- dioxo 65 methyl 17a,20 methylene (20R)5apregnan-2l-oate, 3-cyclic ethylene acetal in chloroform is cooled toabout 5 C., treated with anhydrous hydrogen chloride, recovered from thereaction mixture and recrystallized from ether, in the manner disclosedin Example 15 or 16, above, to give methyl 16,8 hydroxy-3,1l-dioxo-6a-methyl-17a,20-methylene-(20R)-4-pregnen-21-oate.

In the same manner substituting the corresponding trans-(20S) isomer asthe starting steroid in Example 17, there is obtained methyl hydroxy3,11 dioxo-16amethyl-17a,20-methylene-(20S)-4-pregnen-21-oate.

EXAMPLE 18 Methyl 16 8-hydr0xy-3,1I-di0x0-6a-flw0r0-17a,20-methylene-(20R)-4-pregnen-21-0ate A solution of 1.0 g. of methyl5a,16fl-dihydroxy-3,I1- dioxo 6p fluoro ;,20 methylene (20R)5apregnan-Zl-oate, 3-cyclic ethylene acetal in chloroform is cooled toabout 5 C., treated with anhydrous hydrogen chloride, recovered from thereaction mixture and recrystallized from ether in the manner disclosedin EX- ample 6, above, to give methyl 16,8-hydroxy 3,11 dioxo-6ot-fiuoro-17a,20-methylene-(20R)-4-pregnen-21-oate.

In the same manner substituting the corresponding trans-(20S) isomer asthe starting steroid in Example 18, there is obtained methyl 16,8hydroxy 3,11 dioxo-6afluoro-17a,20-methylene-(208)-4-pregnen-21-oate.

In the same manner following the procedure of Examples 15, 16, 17 and18, other compounds of Formulas C and D of this invention can likewisebe converted to the corresponding A -3-oxo compounds. For example:

methyl5a,16a,-dihydroxy-6p,20-dimethyl-3,1l-dioxo-Sapregn-17(20)-cis-en-21-oate,3-cyclic ethylene acetal;

methyl 5a,16u-dihydroxy-6 8-fluoro-20-methyl-3,1l-dioxo-Sec-pregn-l7(20)-cis-en-21-oate, 3 cyclic ethylene acetal;

methyl 5 a-hydroxy-3,1 1, 16-tI'iOX0-613,20-dimfithYl-5apregn-17(20)-cis-en-21-oate, 3-cyclicethylene acetal;

methyl 5a-hydroxy-3,1 1,16-trioxo-6B-fluoro-20-methyl- 5a-pregn-17(20)-cis-en-21-oate, 3-cyclic ethylene acetal;

methyl a,11B-dihydroxy-6B,20-dimethyl-3,16-dioxo-5apregn-17(20)-cis-en-21-oate,3-cyclic ethylene acetal;

methyl 5a,1113,16fl-trihydroxy-6;8,20-dimethyl-3OXO-5apregn-17(20)-cis-en-21-oate, 3-cyclic ethylene acetal;

methyl 50:,11B,16a-trihydroxy-65,20-dimethyl-3-oxo-5a- 5pregn-17(20)-cis-en-21-oate, 3-cyclic ethylene acetal;

methyl 5a,16u-dihydroxy-6B-methyl-3,11-dioxo-17a,20

methylene-(R)-5u-pregnan-2l-oate, 3-cyclic ethylene acetal;

methyl 5a,16a-dihydroXy-3,11-dioxo-6fl-fluoro-17a,20-

methylene-(20R)-5apregnan-2l-oate, 3-cyclic ethylene acetal;

methyl5a-hydroxy-3,11,16-trioxo-6B-methyl-17a,20-methylene-(ZOR)-5a-pregnan-2l-oate,3-cyclic ethylene acetal;

methyl 5a-hydroxy-3, 1 1,16-trioxo-613-fluoro-17a,20-methylene-(20R)-5u-pregnan-21-oate, 3-cyclic ethylene acetal;

methyl 50:,11B-dihydroxy-3,16-dioxo-6fl-methyl-17u,20-methylene-(20R)-5a-pregnan-21-oate, 3-cyclic ethylene acetal;

methyl 5u,11,8,165-trihydroxy-3-oxo-6B-methyl-17a,20-methylene-(20R)-5a-pregnan-21-oate, 3-cyclic ethylene acetal;

methyl 5u,1119,16a-trihydroxy-3-oxo-6fl-methyl-17u,20-methylene-(20R)-5a-pregnan-2l-oate, 3-cyclic ethylene acetal;

and the like to obtain:

methyl 16a-hydroxy-3 ,1 1dioxo-6a,20-dimethylpregn-4, l7

(20)-cis-dien-2l-oate;

methyl 16u-hydroxy-3,11-dioxo-6a-fluoro-20-methylpregn-4,17 (20)-cis-dien-21-oate;

methyl 3,1 1,16-trioxo-6a,20-dimethylpregn-4,17

(20)-cis-dien-21-oate;

methyl 3,11,16-trioxo-6u-fluoro-20-methylpregn-4,17

(20)-cisdien-21-oate;

methyl 11,B-hydroxy-3, l 6-dioxo-6a,20-dimethylpregn-4,l7

(20)-cis-dien-21-oate;

methyl 1 16,16fl-dihydroxy-3 -oxo-6ot,20-dimethylpregn- 4,17(20)-cis-dien-2l-o=ate;

methyl 1 1,8,16a-dihydroxy-3-oxo-65,20-dimethylpregn-4,17(20)-cis-dien-21-oate;

methyl l6a-hydroXy-3 ,1 1-dioxo-6a-methyl-17a,20-

methylene-(20R)-4-pregnen-21-oate;

methyl 16a-hydroxy-3,1 1-dioxo-6a-fluoro-l7a,20-

methylene-(20R)-4-pregr1en-21-oate;

methyl 3,1l,16-trioxo-6a-methyl-17u,20-methylene-(20R)-4-pregnen-21-oate;

methyl 3,11,16-trioxo-6u-fluoro-17a,20-methylene-(20R)-4-pregnen-21-oate;

methyl 1lB-hydroxy-S,16-dioxo-6a-methyl-1711,20-

methylene- (20R) -4-pregneu-2 l -oate;

methyl 1 1,6,16B-dihydroxy-3-oxo6ot-methyl-1711,20-

methylene-(20R)4-pregnen-2l-oate;

methyl 1 1,8,16u-dihydroxy-3-oxo-6a-methyl-17a,20-

methylene-(20R)-4-pregnen-21-oate;

respectively, and the like.

Similarly, the corresponding isomeric trans compounds can likewise beconverted to the corresponding trans A -3-oxo compounds.

EXAMPLE 19 5 0a,] 6f3-dihydr0xy-6 fl,20-dimethyl-3,1 1 -diox0-5a-pregn.-17(20)-cis-en-21-0ic acid, 3-cyclic ethylene acetal was extracted withmethylene chloride and the extract was washed with water until theWashes were neutral to test paper. The extract was dried over anhydroussodium sulfate and concentrated to dryness by distillation in vacuo. Theresidue was crystallized from ether to give in 3 crops, 2.31 g. of50:,1613 dihydroxy 65,20-dimethyl- 3,11 dioxo 5a pregnl7(20)-cis-en-2l-oic acid, 3- cyclic ethylene acetal M.P. 231-233 C. NMRspectra and infrared spectra confirmed the structure.

Analysis.Calcd. for C H O C, 66.94; H, 8.09. Found: C, 66.35; H, 8.13.

In the same manner the other 2l-oic acid alkyl esters of this inventionfor example the compounds represented by Formulas A through H, canlikewise be hydrolyzed to the corresponding 21-free acids. Other esterssuch as 3-acylate groups when present will be converted concomitantly tofree hydroxy.

EXAMPLE 20 Methyl 504,16B-dihydroxy-65,20-dimethyl-3,1Z-dioxo- 5ot-pregn-l 7 (20 -cis-en-21-0ate A solution of 1.0 g. of methyl5a,16B-dihydroxy-6[3,20- dimethyl 3,11 dioxo 50c pregn l7(20)-cis-en-2loate, 3-cyclic ethylene acetal in acetone containing 5 ml. of water and3 crops of 25% aqueous sulfuric acid is allowed to stand for a period ofabout 18 to 24' hours at room temperature. Sodium bicarbonate solutionis then added to neutralize the solution and the solvent is removed invacuo at room temperature until crystallization commences. An additionalml. of Water is added, the temperature is lowered to about 0 C. Thesolid prodnot is collected by filtration and recrystallized fromacetone-Skellysolve B to give methyl $1,165 dihydroxy-65, 20-dimethyl-3,1 1-diOXO-5OL-PI'6gl117(20)-ClS-H-21'Oat.

In the same manner the other compounds of this invention having attached3-cyclic alkylene acetal groups can likewise be converted to thecorresponding free 3- 0x0 compounds. For example, the ZO-methyl and170:,20- methylene-3-cyclic ethylene acetals prepared and listed inExamples 1-14 and 19, above, can be substituted as the starting materialin Example 20 to obtain the corresponding free 3-oxo compounds.

EXAMPLE 21 Methyl 50 dihydroxy-6B,20-dimethyl-3,1l-di0xo5apregn-17(20)-cis-err-21-0ate, 3 cyclic 2,2- dimethyl propane-1,3-di0lacetal A solution of 1.0 g. of methyl 5a,16B-dihydroxy-6fi,20- dimethyl3,11 dioxo 50c pregn 17(20)-cis-en-2loate in 35 ml. of methylenechloride was treated with 1.4 g. of 2,2-dimethyl propane-1,3-diol and 10mg. of toluenesulfonic acid for 20 hours at room temperature. Thereaction mixture was successively washed with-aqueous sodium bicarbonateand water and dried over anhydrous sodium sulfate. The extract wasconcentrated to dryness by distillation in vacuo and the residue wasrecrystallized from boiling ether to give 600 mg. of methyl 50:,165dihydroxy 65,20 dimethyl 3,11 diOXO-Sapregn-17(20)-cis-en-21-oate,3-cyclic 2,2 dimethyl propane-1,3-diol acetal M.P. l95196 C.

Analysis.-Calcd. for C H 0 C, 69.02; H, 8.79. Found: C, 69.17; H, 9.08.

In the same manner substituting methyl 5a,16;3-dihydroxy 6,8 fluoro 20methyl 3,11 diQXo-Su-pregn- 17(20)-cis-en-21-oate as the startingsteroid in Example 21 in place of the corresponding 6/3-methyl compound,is productive of methyl 5a,16;3 dihydroxy 6B fluoro- 20 methyl 3,11dioxo 5a pregn 17(20)-cis-en-21- oate, 3-cyclic 2,2-dimethylpropane-1,3-diol acetal.

EXAMPLE 22 Methyl 5a,16,8dihydroxy-65,20-dimethyl-3,1I-dioxo-Sapregn-17(20)-cis-en-21-oate,3-cyclic trimethylene acetal A solution of 1.0 g. of methyl5a,l6B-dihydroxy-6fi,20- dimethyl 3,11 dioxo 5a pregn 17(20) cis eu-21-oate in 30 ml. of methylene chloride was treated with 1.5 g. ofpropane-1,3-diol and 10 mg. of toluenesulfonic acid for 72 hours at roomtemperature. The reaction mixture was successively washed with aqueoussodium bicarbonate and water and dried over anhydrous sodium sulfate.The extract was concentrated to dryness by distillation in vacuo. Theresidue was chromatographed over 100 g. of Florisil packed inSkellysolve B. The product was eluted with a mixture of 25% acetone inSkellysolve B to give a peak of fractions containing 0.534 g. which wasrecrystallized from diethyl ether-Skellysolve B to give 350 mg. ofmethyl a,16fl-dihydroxy-6 3,20-dimethyl 3,11 dioxo 5a pregn 17(20) cisen 21- oate, 3-cyclic trimethylene acetal M.P. 226228 C.

Analysis.-Calcd. fOI' (337114 071 C, H, Found: C, 68.23; H, 8.46.

In the same manner following the procedure of Examples 21 and 22 otherfree 3-oxo compounds of this invention can likewise be ketalized withthe appropriate alkane 1,2- or 1,3-diol to obtain the desired S-cyclicalkylene acetal.

We claim:

1. A compound selected from the formulas:

R is hydrogen, methyl or fluoro; R is in which R, is an alkylene radicalcontaining up to 8 carbon atoms and the attaching oxygen to carbon bondsare separated by a chain of at least 2 and not more than 3 carbon atoms;X is hydrogen or a lower-alkyl radical of 1 to 8 carbon atoms,inclusive, Y is hydrogen or fluoro and the 1,2-carbon atom linkage is asingle bond linkage or a double bond linkage.

2. A compound selected from the formulas:

R is hydrogen, methyl or fluoro; R is X000 CH I CH2 and H wherein R isin which R is hydroxy or the acyl radical of a hydrocarbon carboxylicacid of 1 to 12 carbon atoms, inclusive,

' and X is hydrogen or a lower-alkyl radical of 1 to 8 carbon atoms,inclusive.

4. A compound selected from the formulas:

XOOC H x000 CH: d!

[\OHQ l R: I R R ]=R I and I R50 RtO wherein R is OH OH 0H OH H =0, or Ris or=0; R1 is or =0 H H H H R is hydroxy or the acyl radical of ahydrocarbon carboxylic acid of 1 to 12 carbon atoms, inclusive, and X ishydrogen or a lower-alkyl radical of V1 to 8 carbon atoms, inclusive.

